Project Summary (do not exceed 30 lines in length) Autoimmune diseases are common human conditions, usually associated to high morbidity because of their chronic duration and usually treated based on their symptoms rather than on their pathogenesis. Autoimmune diseases of the thyroid gland, represented by Graves disease and Hashimoto thyroiditis, are the most common autoimmune diseases. Although most affected patients are treated symptomatically with relative ease, autoimmune thyroid diseases can serve as a model to study other more complex autoimmune diseases. We have developed a mouse model of Hashimoto thyroiditis based on the expression of interferon gamma in the thyroid gland via transgenesis. These mice mimic many features of the human counterpart, including goiter, disrupted thyroid architecture, mononuclear infiltration, oncocytic changes of the thyrocytes, and long-lasting hypothyroidism. The mice have contributed to discover that the thyroid cells affected by autoimmunity express elevated levels of a protein, called LMP2, which is a component of a proteolytic machinery called immunoproteasome. They have also showed that the thyroid becomes heavily infiltrated by macrophages suggesting a role for these cells in disease pathogenesis. The present proposal mainly aims to characterize the role of LMP2 and macrophages in autoimmune thyroiditis.